Project summary Thoracic aortic aneurysms (TAA) are life-threatening pathologies characterized by progressive dilation associated with smooth muscle cell dysfunction and destructive extracellular matrix remodeling that ultimately lead to tear and rupture of the vessel wall. Current management of TAA relies on early detection by routine imaging and prophylactic repair by surgical procedures. The main goal of this proposal is to use systems therapeutics as an unbiased tissue-level strategy to identify combinatorial treatments with repurposed drugs that can efficaciously target TAA-related signaling pathways in mice with early onset, progressively severe Marfan syndrome (MFS). This genetic model of TAA was chosen because the mutated protein (fibrillin-1) regulates several key aspects of arterial function and homeostasis, including tissue integrity, endothelial cell mechanotransduction, and angiotensin II and TGF? signaling. Our proposal is organized into two specific aims that combine experimental and computational approaches to elucidate the pathogenic contributions of multiple signaling pathways and cell types in the fibrillin-1-deficient aortas of MFS mice (Aim 1); and predict and validate combinatorial drug treatments targeting disease-associated signals within and across distinct wall compartments (Aim 2). Our system therapeutics strategy is expected to transform MFS from a deadly arterial disease that requires surgical intervention to a chronic condition that can be managed medically.